P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac
| Autor: | Patrick T. Ronaldson, Lucy Sanchez-Covarrubias, Brandon J. Thompson, Lauren M. Slosky, Yifeng Zhang, Thomas P. Davis, Mei Li Laracuente, Kristin M. DeMarco |
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| Rok vydání: | 2013 |
| Předmět: |
Central Nervous System
Nociception Anatomy and Physiology Glycobiology lcsh:Medicine Fluorescent Antibody Technique Pharmacology Carrageenan Cardiovascular Biochemistry Rats Sprague-Dawley Transmembrane Transport Proteins 0302 clinical medicine Anesthesiology Edema Drug Interactions lcsh:Science 0303 health sciences Multidisciplinary Morphine Anti-Inflammatory Agents Non-Steroidal Animal Models 3. Good health medicine.anatomical_structure Neurology Blood-Brain Barrier Hyperalgesia Medicine Female medicine.symptom medicine.drug Research Article Drugs and Devices Diclofenac Cognitive Neuroscience Cerebrovascular Diseases Analgesic Pain Blood–brain barrier Neurological System 03 medical and health sciences Model Organisms Neuropharmacology Vascular Biology medicine Animals Pain Management ATP Binding Cassette Transporter Subfamily B Member 1 Biology 030304 developmental biology Glycoproteins business.industry Tumor Necrosis Factor-alpha lcsh:R Proteins Biological Transport Rats Mechanism of action Microvessels Rat lcsh:Q business 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 2, p e88516 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Our laboratory has previously demonstrated that peripheral inflammatory pain (PIP), induced by subcutaneous plantar injection of λ-carrageenan, results in increased expression and activity of the ATP-dependent efflux transporter P-glycoprotein (P-gp) that is endogenously expressed at the blood-brain barrier (BBB). The result of increased P-gp functional expression was a significant reduction in CNS uptake of morphine and, subsequently, reduced morphine analgesic efficacy. A major concern in the treatment of acute pain/inflammation is the potential for drug-drug interactions resulting from P-gp induction by therapeutic agents co-administered with opioids. Such effects on P-gp activity can profoundly modulate CNS distribution of opioid analgesics and alter analgesic efficacy. In this study, we examined the ability of diclofenac, a non-steroidal anti-inflammatory drug (NSAID) that is commonly administered in conjunction with the opioids during pain therapy, to alter BBB transport of morphine via P-gp and whether such changes in P-gp morphine transport could alter morphine analgesic efficacy. Administration of diclofenac reduced paw edema and thermal hyperalgesia in rats subjected to PIP, which is consistent with the known mechanism of action of this NSAID. Western blot analysis demonstrated an increase in P-gp expression in rat brain microvessels not only following PIP induction but also after diclofenac treatment alone. Additionally, in situ brain perfusion studies showed that both PIP and diclofenac treatment alone increased P-gp efflux activity resulting in decreased morphine brain uptake. Critically, morphine analgesia was significantly reduced in animals pretreated with diclofenac (3 h), as compared to animals administered diclofenac and morphine concurrently. These novel findings suggest that administration of diclofenac and P-gp substrate opioids during pain pharmacotherapy may result in a clinically significant drug-drug interaction. |
| Databáze: | OpenAIRE |
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